3D printing of self-healing personalized liver models for surgical training and preoperative planning

3D printing can produce intuitive, precise, and personalized anatomical models, providing invaluable support for precision medicine, particularly in areas like surgical training and preoperative planning. However, conventional 3D printed models are often significantly more rigid than human organs and cannot undergo repetitive resection, which severely restricts their clinical value. Here we report the stereolithographic 3D printing of personalized liver models based on physically crosslinked self-healing elastomers with liver-like softness. Benefiting from the short printing time, the highly individualized models can be fabricated immediately following enhanced CT examination. Leveraging the high-efficiency self-healing performance, these models support repetitive resection for optimal trace through a trial-and-error approach. At the preliminary explorative clinical trial (NCT06006338), a total of 5 participants are included for preoperative planning. The primary outcomes indicate that the negative surgery margins are achieved and the unforeseen injuries of vital vascular structures are avoided. The 3D printing of liver models can enhance the safety of hepatic surgery, demonstrating promising application value in clinical practice.


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The present work deals with 3 d printed, self-healing elastomers, and shows a possible application case for preoperative planning.This is a very interesting and promising work.It focuses more or less on three topicsmaterial processing/printing, self-healing, and application on preoperative models.The processing/printing and self welding are recently presented in a similar form by the authors of this paper.The application for surgical training models on a human liver is original.
The basic question arises to whom this work is addressed (Chemical or biomedical engineers, medical experts), a clear focus and objective are missing.
The parts are not strongly connected and written differently.The novel part is the usage of the model for surgical training.Thus the review focuses mainly on that.If also the other parts contain novelty, it should be clearly stated how this work differs from previous studies.
Important information about the surgical model topic is missing, and more details would be helpful (see comments).Overall, this is a relevant work, but it is suggested to rethink the objectives as well as the focus and revising the work.

Detailed Comments
Models for surgical training: The authors focus here on 2 important features that such models should have -stiffness and self-healing.However, there are a number of other important aspects that have not been addressed here: 1)Stiffness: This aspect is much more complex than presented here.Liver is a non-linear viscous material that cannot be simply described with one tensile test and one elastic Emodulus (how was this measured and evaluated?).There are several way to describe such a material, but also viscous parameters are important that have not been mentioned.Is the new material rather visco-elastic-plastic or is it hyperelastic?Especially for the haptic behavior not only the initial compliance but also the stiffening behavior during "pressing" and the viscous behavior in terms of hysteresis is important for the "feeling".These things have been studied recently extensively, specifically on the liver, but not considered or mentioned here.Is recommend to do a comprehensive literature study in this direction.A cycling experiment should be done to show that this material is similar to liver and outperforms currently used materials like soft 3D printing material (e.g. from Stratasys) or silicones for such surgical models.
2) Pre-operative planning: Important requirements for such models are a simple/fast manufacturability, similar mechanical behavior as the biological tissue, but also the possibility of manipulation.In addition to cutting with a scalpel (presented here but not well described), electro-cutting, and suturing (pulling out) are also very important features.The question is how the new material performs in the latter two as well as how realistic is the cutting with a scalpel -is there an feedback from surgent?
3)In this work, a model which is only 50% of the original size was used and there is no information about the real costs of a 3D print although the authors claim to produce a "similar to reality" and cost-effective model.A new feature of the material which is very interesting is the repetitive cutting option.However, in some case this could be a disadvantage e.g. when slipping of surfaces is important like in joints.4) In many cases of surgical models, 3D Printing is not the first method of choice, casting is much faster to fabricate big parts.3D printing makes sense for tiny, hollow, microstructured parts or vessels, etc. this aspect should be also discussed when talking about surgical training models.5) How good is the material really compared to other materials?i.e.Hydrogel vs. Silikon vs. soft 3D printed material vs. real liver: It would be also interesting to see a comparison of typical artificial materials as well as a comparison to real liver tissue wrt to the abovementioned points.Especially how about the handling properties (sticking to cloughs) and drying out of hydrogels.6) Toxity, environmental compatibility, and recycling: Could you give any statements on that?L188: It is not clear how exactly the model was created.It seems individual parts are printed, and the model is assembled and filled with liquid.If the focus of a revised work is on surgical models, more details should be given in this part.One aspect not mentioned in this context -how about self-healing of separately printed parts?There was work published which shows a different behavior if cut surfaces or other outer-surfaces are glued together.
I guess there are also limitations which should be described.

Reviewer #1 (Remarks to the Author):
The authors report the self-healing elastomers via stereolithographic 3D printing from copolymerization of 4-acryloylmorpholine (ACMO) and methyl poly (ethylene glycol) acrylate (mPEGA).The elastomers exhibit tunable modulus and efficient self-healing capability.It is shown that the printed liver models based on the elastomers have liverlike modulus and can facilitate the achievement of tumor-free surgical margin and the protection of important anatomical structures via a trial-and-error method.This work is interesting and the result has promising application.

Answer:
We thank the reviewer for the positive comments.
Q1.The innovation of this work is not so strong, as this kind of self-healing elastomers based on hydrogen bond interactions is widely reported.
Answer: We thank the reviewer for the comment.Just as the reviewer said, self-healing elastomers based on hydrogen bond interactions have been widely reported.However, there is barely real practical application of self-healing materials reported.Also, most of the previous work focuses only on the mechanism and performance of the selfhealing capacity.Our work aims at developing self-healing and re-cuttable liver models for surgical training and preoperative planning.So, several specialized criteria should be meet.First, the elastomer should be self-healed efficiently at room temperature within several minutes.Second, considering the practicality, it is better to use commercialized raw materials in order to keep a low cost, complex synthesis process is not preferred here.Third, the precursor of the elastomer should have a low viscosity and a high reactivity to guarantee an efficient 3D printing.To the best of our knowledge, no previously reported self-healing elastomer can satisfy all these demands at the same time.In this work, two commercial monomers are used to get a liquid resin with high reactivity and ultra-low viscosity in the absence of any chemical crosslinkers.Indeed, such a DLP 3D printed thermoplastic self-healing elastomer has not been reported yet.Hydrogen bond interaction and the linear chain topology together contribute to the efficient self-healing at room temperature.We find that introduction of a small amount of chemical crosslinker or other monomers which can not form hydrogen bond with ACMO will both significantly decline the self-healing performance (Fig. 3c).
Q2.The authors emphasize only the importance of liver-like modulus for liver models, except modulus, what other properties of the elastomers should be taken into account when used for liver modulus?Q.2 The authors report the two cases here using the 3D printed liver.Do the authors have measurable/objective data in terms of how has the use of the 3D printed liver made the hepatic resection safer or easier or more efficient or easier to teach?Answer: We thank the reviewer for the comment.To explore the feasibility of 3D printed liver models for preoperative planning, a phase 1, preliminary interventional study is registered on ClinicalTrials.gov(ID: NCT06006338).In this study, a total of 5 models were employed by experienced surgeons for preoperative planning purposes.The highly personalized models can be printed soon after preoperative enhanced CT examination and perspective planning can be implemented on the model before the authentic surgery.According to surgeons' feedback, the addition of a physical model facilitated a clearer and more vivid comprehension of the personalized features of a tumor.More importantly, the try-and-error method allowed them to determine the optimal surgical plane.In the majority of cases, surgeries were successfully carried out without interruption, adhering to the pre-planned surgical approach.There was no need to pause the surgery, review CT/MRI data, or conduct intraoperative ultrasound, as had been required in previous operations.In a word, preoperative planning on models makes the hepatic resection safer by maximizing the degree of certainty and minimizing the possibility of emergency situations, which is hard to achieved by previously reported 3D printed models and other 3D visualization methods.However, it should note that this study did not include a control group because the clinical outcomes are difficult to measure quantitatively.Prospective randomized controlled trails will be addressed in future research endeavors.

Q.3 Could the authors discuss in more detail the limitations of the paper?
Answer: In this work, we try to propose a 3D printed precise liver model which exhibit a repetitive cutting capability to be applied in surgical training and personalized preoperative planning.To achieve this goal, we develop a low-cost, highly reactive, self-healing elastomer with tailorable mechanical properties.Preliminary trials in clinical practice demonstrate that this self-healing model allows surgeons to determine optimal operation traces via repeating surgical simulations on the printed models.However, just as proposed by the reviewers, the previous version of the manuscript does have limitations in the aspects of material, process, and application.1.We emphasized only the importance of modulus for liver models, and failed to notice that the liver is a non-linear viscous material.We have systematically investigated the viscoelasticity of the material and added the results in the revised manuscript.The results show that the mechanical properties of the self-healing elastomer can be easily tailored to get close to the real biomechanical characteristics of the liver.2. Limited by the available printing size of our 3D printer, we can only print a half-size liver model.We have already started to customize a larger DLP 3D printer, but it will take some time.3. Considering the difficulty of manufacturing in the present experimental conditions, the model is simplified, and only includes liver, tumor, hepatic vein, and portal vein.If other structures (such as the abdominal cavity, the retrohepatic inferior vena cava, and the gall bladder) can be produced and assembled together with the printed liver model, this technology will be more in line with real-life surgical setting and have broader clinical prospects.With the improvement in printing accuracy of 3D printers and the optimization of our materials, I believe that this problem can be resolved in the near future.

Reviewer #3 (Remarks to the Author):
Summary ======= The present work deals with 3d printed, self-healing elastomers, and shows a possible application case for preoperative planning.This is a very interesting and promising work.It focuses more or less on three topicsmaterial processing/printing, self-healing, and application on preoperative models.The processing/printing and self-welding are recently presented in a similar form by the authors of this paper.The application for surgical training models on a human liver is original.
The basic question arises to whom this work is addressed (Chemical or biomedical engineers, medical experts), a clear focus and objective are missing.
The parts are not strongly connected and written differently.The novel part is the usage of the model for surgical training.Thus, the review focuses mainly on that.If also the other parts contain novelty, it should be clearly stated how this work differs from previous studies.
Important information about the surgical model topic is missing, and more details would be helpful (see comments).Overall, this is a relevant work, but it is suggested to rethink the objectives as well as the focus and revising the work.

Detailed Comments
Models for surgical training: The authors focus here on 2 important features that such models should have -stiffness and self-healing.However, there are a number of other important aspects that have not been addressed here: Q1.Stiffness: This aspect is much more complex than presented here.Liver is a nonlinear viscous material that cannot be simply described with one tensile test and one elastic E-modulus (how was this measured and evaluated?).There are several ways to describe such a material, but also viscous parameters are important that have not been mentioned.Is the new material rather visco-elastic-plastic or is it hyperelastic?Especially for the haptic behavior not only the initial compliance but also the stiffening behavior during "pressing" and the viscous behavior in terms of hysteresis is important for the "feeling".These things have been studied recently extensively, specifically on the liver, but not considered or mentioned here.Is recommend to do a comprehensive literature study in this direction.A cycling experiment should be done to show that this material is similar to liver and outperforms currently used materials like soft 3D printing material (e.g. from Stratasys) or silicones for such surgical models.

Answer:
We agree with the reviewer's comment.We admit that it is not enough to emphasize only the importance of liver-like modulus for liver models.Other properties of the elastomers should be considered when used for liver modulus.According to the reviewer's suggestion, viscoelastic properties of the self-healing elastomer have been systematically investigated and added in the revised manuscript (Fig. 2e-h).Hysteretic curves, G'/G'', stress relaxation, and shape recovery have been studied through cyclic tensile test, shear rheology test, and dynamic mechanical analysis.On the whole, all the results show that the self-healing elastomer is not a hyper-elastic material.Nonnegligible energy loss derived from the intrinsic viscosity of the material can be observed when it is deformed.This is coincident with the biomechanical characteristics of liver [1][2][3] .The viscoelasticity of the elastomers can be tuned through the adjustment of the composition to simulate a human liver as much as possible (Fig. 2i).
Q2. Pre-operative planning: Important requirements for such models are a simple/fast manufacturability, similar mechanical behavior as the biological tissue, but also the possibility of manipulation.In addition to cutting with a scalpel (presented here but not well described), electro-cutting, and suturing (pulling out) are also very important features.The question is how the new material performs in the latter two as well as how realistic is the cutting with a scalpel -is there a feedback from surgent?Answer: We thank the reviewer for the comment.The ultrasound scalpel is one of the most commonly used cutting device, and is routinely used to resect a tumor from the liver by the surgeons of our team in their center.The active blade of an ultrasonic scalpel can make ultra-high frequency oscillations and produce frictional heat, so that liver parenchyma is divided and the container vessels are sealed.The material used in this study can be easily cut by an ultrasound scalpel, and we have compared the changes of related parameters when the material was cut using an ordinary scalpel and an ultrasound scalpel (Fig. 4b).It turned out that changes were similar in both conditions.Besides, according to the feedback of surgeons in our team, it brought similar feels in terms of cutting resistance or heat changes when they cut the liver parenchyma of a patient and the printed model with an ultrasound scalpel.They also experienced analogous feeling when making suturing movements in the liver parenchyma of a patient and the printed model.Q3.In this work, a model which is only 50% of the original size was used and there is no information about the real costs of a 3D print although the authors claim to produce a "similar to reality" and cost-effective model.A new feature of the material which is very interesting is the repetitive cutting option.However, in some case this could be a disadvantage e.g. when slipping of surfaces is important like in joints.